By Helen K. Kelley
Genomic medicine, a discipline that involves using an individual’s genomic information as part of their clinical care, is true personalized medicine. Physicians and researchers in this field are working diligently to find new treatments that customize a patient’s medical care based on their unique genetic makeup.
Rapid Advances in Genetic Disease Research
“This is an exciting time in the field of genetic disease research,” says William R. Wilcox, M.D., Ph.D., professor of human genetics and pediatrics at Emory University School of Medicine. “There’s no question, we’re advancing quickly.”
Wilcox says there are three specific areas in genomic medicine that are making rapid progress and are poised to make a significant impact on certain populations:
1 Newborn screening. “In Georgia, we are conducting pilot screening for different disorders with National Institutes of Health (NIH) funding. These screens are for rare disorders that often are missed by healthcare providers or are only diagnosed after permanent damage has occurred,” Wilcox explains.
One example is spinal muscular atrophy (Werdnig-Hoffman disease). “There is a treatment available now that can prevent this disorder from developing if you identify it at the newborn stage,” he says.“These pilot screening programs are a joint effort between Emory University and the Georgia Public Health Laboratory. I’m proud that Georgia is one of the national leaders in this effort.”
2 Diagnostics. “We’re increasingly able to provide the answer as to why a child or an adult with an often bizarre group of symptoms has them – we can come to a specific diagnosis. For example, we are becoming more successful in identifying what causes significant learning disabilities or autism,” Wilcox says.
“We can figure out why it happened from a genetic perspective because of advances in molecular testing that have occurred over the last few years,” he adds. “In the not too distant future, I think we will be moving from the research we’re currently doing to full genome sequencing at a more reasonable cost.”
3 Treatment. Dr. Wilcox says that his colleagues at Emory, Children’s Healthcare of Atlanta (CHOA) and across the country are participating in a significant amount of research to provide new treatments for various genetic diseases.
“We’re learning how to treat disorders like sickle cell disease and hemophilia through clinical trials that involve processes like removing hematopoietic stem cells from the patient, making modifications and then putting them back in. Or we can give an intravenous infusion that can be targeted to help a specific organ, such as delivering a missing enzyme that isn’t being produced,” he says. “There is now even a drug to treat spinal muscular atrophy that can be delivered through a peripheral IV infusion that is able to cross the blood-brain barrier and provide a functional gene to the motor nerve cells. We are advancing rapidly in our knowledge of treatments for genetic diseases.”
When asked what he predicts for the future of genomics, Wilcox says he thinks research will continue to evolve, providing increased efficiency of treatments at lower costs.
“For genetic screening, the sequencing technologies are getting cheaper and more organized,” he says. “It may be that one day, we all have our genome sequencing done and then carry it around with us on a flash drive. You’ll know what genes you carry and what treatments you need.”
In the News: Researchers Discover Roles and Teamwork of CRISPR-Cas Proteins
Recently published research from the University of Georgia and UConn Health provides new insight about the basic biological mechanisms of the RNA-based viral immune system known as CRISPR-Cas.
CRISPR-Cas, short for Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated, is a defense mechanism that has evolved in bacteria and archaea that these single-celled organisms use to ward off attacks from viruses and other invaders. When a bacterium is attacked by a virus, it makes a record of the virus’s DNA by chopping it up into pieces and incorporating a small segment of the invader’s DNA into its own genome. It then uses this DNA to make RNAs that bind with a bacterial protein that then kills the viral DNA.
The system has been studied world- wide in hopes that it can be used to edit genes that predispose humans to countless diseases, such as diabetes and cancer. However, to reach this end goal, scientists must gain further understanding of the basic biological process that leads to successful immunity against the invading virus.
“This research is more fundamental and basic than studies that are trying to determine how to use CRISPR for therapeutic or biomedical application,” says Michael Terns, principal investigator for the project. “Our study is about the unique first step in the process, known as adaptation, where fragments of DNA are recognized and integrated into the host genome and provide immunity for future generations.”
Previously, it was not understood how the cell recognized the virus as an invader, nor which bacterial proteins were necessary for successful integration and immunity. Through this study, researchers were able to determine how the bacterial immune system creates a molecular memory to remove harmful viral DNA sequences and how this is passed down to the bacterial progeny.
By looking at patterns in the data, the researchers discovered several new findings about how two previously poorly characterized Cas4 proteins function in tandem with Cas1 and Cas2 proteins found in all CRISPR-Cas systems.
In this initial adaptation phase, one of two different Cas4 proteins recognizes a signaling placeholder in the sequence that occurs adjacent to the snippet of DNA that is excised.
When the Cas1 and Cas2 proteins are present in the cell with either of two Cas4 protein nucleases, Cas4-1 and Cas4-2, they act like the generals of this army-based immune system, communicating uniform-sized clipped DNA fragments, directions on where to go next and ultimately instructions that destroy the lethal DNA fragment.
For a cell to successfully recognize and excise strands of DNA, incorporate them into its own genome and achieve immunity, the Cas4 proteins must be present in conjunction with the Cas1 and Cas2 proteins.
To achieve these findings, the research team from the University of Georgia created strains of archaeal organisms with key genetic deletions. Hundreds of millions of DNA fragments captured in the CRISPR loci were sent to the Graveley lab in Farmington, Conn., where they were sequenced with the Illumina MiSeq system. The researchers then used supercomputing for bioinformatics analysis and data interpretation.
While there is still much to learn about the biological mechanisms involved in CRISPR-Cas systems, this research tells scientists more about the way these proteins work together to save the cell and achieve immunity.
In the News: NIH Completes In-depth Genomic Analysis of 33 Cancer Types
Researchers funded by the National Institutes of Health have completed a detailed genomic analysis, known as the PanCancer Atlas, on a data set of molecular and clinical information from more than 10,000 tumors representing 33 types of cancer.
“This project is the culmination of more than a decade of groundbreaking work,” says NIH Director Francis S. Collins, M.D., Ph.D. “This analysis provides cancer researchers with unprecedented understanding of how, where and why tumors arise in humans, enabling better informed clinical trials and future treatments.”
The PanCancer Atlas, published as a collection of 27 papers across a suite of Cell journals, sums up the work accomplished by The Cancer Genome Atlas (TCGA), a multi-institution collaboration initiated and supported by the National Human Genome Research Institute (NHGRI) and the National Cancer Institute (NCI), both part of NIH. The program, with more than $300 million in total funding, involved upwards of 150 researchers at more than two dozen institutions across North America.
The project focused not only on cancer genome sequencing, but also on different types of data analyses, such as investigating gene and protein expression profiles, and associating them with clinical and imaging data.
The PanCancer Atlas is divided into three main categories, each anchored by a summary paper that recaps the core findings for the topic. The main topics include cell of origin, oncogenic processes and oncogenic pathways. Multiple companion papers report in-depth explorations of individual topics within these categories.
The entire collection of papers comprising the PanCancer Atlas is available through a portal on cell.com. Additionally, as the decade-long TCGA effort wraps up, there will be a three-day symposium, TCGA Legacy: Multi-Omic Studies in Cancer, in Washington, D.C., September 27-29, 2018, that will discuss the future of large-scale cancer studies, with a session focusing on the PanCancer Atlas. The meeting will feature the latest advances on the genomic architecture of cancer and showcase recent progress toward therapeutic targeting.